Ligand-mediated conformation diversity of Hsp90 revealed by GaMD simulations and Markov model

Ligand-mediated conformation diversity of Hsp90 revealed by GaMD simulations and Markov model | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Ligand-mediated conformation diversity of Hsp90 revealed by GaMD simulations and Markov model Huayin Bao, Jian Wang, Lu Zhao, Jianzhong Chen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6768733/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Nov, 2025 Read the published version in Molecular Diversity → Version 1 posted 12 You are reading this latest preprint version Abstract The conformational plasticity of Hsp90 is crucial for understanding its function and drug design. In this study, Gaussian accelerated molecular dynamics (GaMD) simulations followed by Markov model analysis were performed to investigate how the ligands D57, 9QY, and 2GJ affect the in- and out-states of the region between α41 and α42 in Hsp90. Our results showed that binding of these ligands reduces the number of conformational states, especially for 2GJ. Specifically, the conformational transition in Hsp90 bound by D57 in the in-state occurs more readily than that in Hsp90 bound by 9QY in the out-state Hsp90. Principal component analysis (PCA) indicated that the impact of D57 on the conformational fluctuations of α41 in the in-state differs from the effects of 9QY and 2GJ on this helix in the out-state Hsp90. This difference can likely be explained by the variations in network communication caused by these ligands. Furthermore, our analysis of hot spots revealed that the different interactions of D57, 9QY, and 2GJ with residues L48, K58, D93, F183, and T184 are possibly responsible for their distinct conformational plasticity. We hope that this work can provide valuable theoretical insights for designing drugs targeting Hsp90. Hsp90 conformational diversity GaMD simulation Markov model correlation network analysis Full Text Additional Declarations No competing interests reported. Supplementary Files supportinginformation.docx Cite Share Download PDF Status: Published Journal Publication published 11 Nov, 2025 Read the published version in Molecular Diversity → Version 1 posted Editorial decision: Revision requested 13 Aug, 2025 Reviews received at journal 29 Jul, 2025 Reviews received at journal 19 Jun, 2025 Reviewers agreed at journal 17 Jun, 2025 Reviews received at journal 16 Jun, 2025 Reviewers agreed at journal 12 Jun, 2025 Reviewers agreed at journal 10 Jun, 2025 Reviewers agreed at journal 10 Jun, 2025 Reviewers invited by journal 10 Jun, 2025 Editor assigned by journal 29 May, 2025 Submission checks completed at journal 29 May, 2025 First submitted to journal 28 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6768733","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":469527867,"identity":"b4af6e04-4355-429e-9c44-dcfecffef952","order_by":0,"name":"Huayin Bao","email":"","orcid":"","institution":"Shandong University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Huayin","middleName":"","lastName":"Bao","suffix":""},{"id":469527868,"identity":"83e6ad37-383a-4062-95dd-1565aff83835","order_by":1,"name":"Jian Wang","email":"","orcid":"","institution":"Shandong Jiaotong 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